A Brain-Enhanced Chemical Delivery System for Gonadal Steroids: Implications for Neurodegenerative Diseases

  • James W. Simpkins
  • Mohamad H. Rahimy
  • Nicholas Bodor
Part of the Advances in Behavioral Biology book series (ABBI, volume 36)


The brain is a primary target for the physiological and pharmacological actions of gonadal steroid hormones. These hormones exert two modes of action on the brain: (i) during the critical period of fetal/neonatal life these hormones affect permanently some features of the brain structure and function which result in neuronal differentiation and (ii) during the adult life exert their effects in a modulatory, reversible mode that influence adult brain function.


Luteinizing Hormone Cholinergic Neuron Gonadal Steroid Daily Food Intake Luteinizing Hormone Secretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    C. Lauritzen, The management of the pre-menopausal and the postmenopausal patient, in: “Aging and Estrogens,” P.A. Van Keep and C. Lauritzen, eds., Karger, Basel (1973).Google Scholar
  2. 2.
    S. Campbell and M. Whitehead, Oestrogen therapy and the menopausal syndrome, Clin. Obstet. Gvnaecol. 4: 31 (1977).Google Scholar
  3. 3.
    H.L. Judd, Pathophysiology of menopausal hot flushes, in: “Neuroendocrinology of Aging,” J. Meites, ed., Plenum press, New York (1983).Google Scholar
  4. 4.
    B.B. Sherwin, Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women, Psychoneuroendocrinolooy 13: 345 (1988).CrossRefGoogle Scholar
  5. 5.
    I. Persson, The risk of endometrial and breast cancer after estrogen treatment, Acta. Obstet. Gvnecol. Scand. 130 Suppl.: 59 (1985).Google Scholar
  6. 6.
    D.B. Thomas, Steroid hormones and medications that alter cancer risks, Cancer 62: 1755 (1988).CrossRefGoogle Scholar
  7. 7.
    W.M. Pardridge, J.D. Connor and I.L. Crawford, Permeability changes in the blood-brain barrier: causes and consequences, CRC Crit. Rev. Toxic. 3: 159 (1975).Google Scholar
  8. 8.
    E. Levin, Are the terms blood-brain barrier and brain capillary permeability synonymous, Exp. Eve Res. 25 Suppl.: 191 (1977).Google Scholar
  9. 9.
    B. Van Duers, Structural aspects of brain barriers with special reference to the permeability of the cerebral endothelium and choroidal epithelium, Int. Rev. Cvtol. 65: 117 (1980).CrossRefGoogle Scholar
  10. 10.
    H. Dayson, The blood-brain barrier, J. Physiol. Lond. 255: 1 (1976).Google Scholar
  11. 11.
    N. Bodor and M.E. Brewster, Problems of delivery of drugs to the brain, Pharmacol. Therapeut. 19: 337 (1983).CrossRefGoogle Scholar
  12. 12.
    M.J. Karnovsky, The ultrastructural basis of capillary permeability studies with peroxidase as a tracer, J. Cell Biol. 35: 213 (1967).CrossRefGoogle Scholar
  13. 13.
    T.S. Reese and M.J. Karnovsky, Fine structural localization of a blood-brain barrier to exogenous peroxidase, J. Cell Biol. 34: 207 (1967).CrossRefGoogle Scholar
  14. 14.
    M.W. Brightman and T.S. Reese, Junctions between intimately opposed cell membranes in the vertebrate brain, J. Cell Biol. 40: 648 (1969).CrossRefGoogle Scholar
  15. 15.
    W.H. Oldendorf, The blood-brain barrier, EXD. Eye Res. 25 Suppl.: 177 1 (1977).Google Scholar
  16. 16.
    R.R. Shivers, The blood-brain barrier of a reptile, Anoli’s, Carolinensis. A freeze-fracture study, Brain Res. 169: 221 (1979).CrossRefGoogle Scholar
  17. 17.
    M.W. Brightman, Morphology of blood-brain interfaces, Exp. Eye Res. 25 Suppl.: 1 (1977).Google Scholar
  18. 18.
    R.D. Broadwell and. M. Saloman, Expanding the definition of the blood-brain barrier to protein, Proc. Soc. Acad. Sci. U.S.A. 78: 7820 (1981).CrossRefGoogle Scholar
  19. 19.
    J.E. Hardebo, B. Falck, C. Owman and E. Rosengren, Studies on the enzymatic blood-brain barrier: quantitative measurement of DOPA decarboxylase in the wall of microvessels as related to the parenchyma in various CNS regions, Acta Physiol. Scand. 105: 453 (1979).CrossRefGoogle Scholar
  20. 20.
    J.E. Hardebo and C. Owman, Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface, Ann. Neurol. 8: 1 (1980).CrossRefGoogle Scholar
  21. 21.
    G.P. Kaplan, B.K. Hartman and C.R. Creveling, Immunohistochemical localization of catechol-o-methyltransferase in circumventricular organ of the rat: potential variations in the blood-brain barrier to native catechols, Brain Res. 229: 323 (1981).CrossRefGoogle Scholar
  22. 22.
    W.H. Oldendorf, L. Braun, S. Hyman and S.Z. Oldendorf, Blood-brain barrier: penetration of morphine, codeine, heroin and methadone after carotid injection, Science 178: 984 (1972).CrossRefGoogle Scholar
  23. 23.
    J.M. Cruickshank, G. Neil-Dwyer, M.M. Cameron and J. McAinsh, Badrenoreceptor-blocking agents and the blood-brain barrier, Clin. Sci. 59: 453s (1979).Google Scholar
  24. 24.
    V.A. Levin, Relationship of octanol water partition coefficients and molecular weight to rat brain capillary permeability, J. Med. Chem. 23: 682 (1980).CrossRefGoogle Scholar
  25. 25.
    A.A. Sinkula and S.H. Yalkowsky, Rational for design of biologically reversible drug derivatives: Prodrugs, J. Pharm. Sci. 64: 181 (1975).CrossRefGoogle Scholar
  26. 26.
    N. Bodor, The soft drug approach, Chemtech Jan: 28 (1984).Google Scholar
  27. 27.
    N. Bodor, Novel approaches in prodrug design, Drugs of the future 6: 165 (1981).Google Scholar
  28. 28.
    N. Bodor, Soft drugs: Principles and methods for the design of safe drugs, Med. Res. Reviews 4: 449 (1984).CrossRefGoogle Scholar
  29. 29.
    V. Stella, Pro-drugs: an overview and definition, in: “Prodrugs as Novel Drug Delivery Systems,” T. Higuchi and V. Stella, eds., ACS Symposium Series Vol. 14, American Chemical Society, Washington, D.C. (1975).Google Scholar
  30. 30.
    R.D. Smyth, M. Pfeffer, D.R. Van Hanker, A. Cohen and G.H. Hottendorf, Human pharmacokinetics and disposition of sarmoxicillin, a lipophilic amoxicillin prodrug, Antimicrob. Ag. Chemother. 1004 (1981).Google Scholar
  31. 31.
    H. Ferres, Pro-drugs of 8-lactam antibiotics, Chem. Ind. 11: 436 (1980).Google Scholar
  32. 32.
    T.A. Connors, Possible pro-drugs in cancer chemotherapy, Chem. Ind. 11: 447 (1980).Google Scholar
  33. 33.
    M. Masquelier, R. Baurain and A. Trouet, Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, Physicochemical properties, and lysosomal digestion, J. Med. Chem. 23: 1166 (1980).CrossRefGoogle Scholar
  34. 34.
    P. Workman and J.A. Double, Drug Latentiation in Cancer Chemotherapy, Biomed. 28: 255 (1978).Google Scholar
  35. 35.
    N. Bodor, E. Shek and T. Higuhi, Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative, Science 190: 155 (1975).CrossRefGoogle Scholar
  36. 36.
    N. Bodor, H. Farag and M.E. Brewster, site-specific sustained release of drugs to the brain, Science 214: 1370 (1981).CrossRefGoogle Scholar
  37. 37.
    N. Bodor and H. Farag, Improved delivery through biological membranes XI. A redox chemical drug delivery system and its use for brain specific delivery of phenethylamine, J. Med. Chem. 26:313 (1983).Google Scholar
  38. 38.
    N. Bodor and J.W. Simpkins, Redox delivery system for brain-specific, sustained release of dopamine, Science 221: 65 (1983).CrossRefGoogle Scholar
  39. 39.
    J.W. Simpkins, N. Bodor and A. Enz, Direct evidence for brain specific release of dopamine from a redox delivery system, J. Pharm. Sci. 94: 1033 (1985).CrossRefGoogle Scholar
  40. 40.
    N. Bodor and H. Farag, Improved delivery through biological membranes XIII. Brain specific delivery of dopamine with a dihydropyridine pyridinium salt type redox delivery system, J. Med. Chem. 26: 528 (1983).CrossRefGoogle Scholar
  41. 41.
    N. Bodor and M.E. Brewster, Improved delivery through biological membranes, XV. Sustained brain delivery of berberine, Eur. J. Med. Chem. 18: 235 (1983).Google Scholar
  42. 42.
    W.R. Anderson, J.W. Simpkins, P.A. Woodard, D. Winwood, W.C. Stern and N. Bodor, Anxiolytic activity of a brain delivery system for GABA, Psychopharmacology 92: 157 (1987).CrossRefGoogle Scholar
  43. 43.
    M.H. Rahimy, N. Bodor and J.W. Simpkins, A rapid, sensitive method for the simultaneous quantitation of estradiol and estradiol conjugates in a variety of tissues: assay development and evaluation of the distribution of a brain-enhanced estradiol-chemical delivery system, J. Steroid Biochem. 33: 000 (1989).CrossRefGoogle Scholar
  44. 44.
    G. Mullersman, H. Derendorf, M.E. Brewster, K.S. Estes and N. Bodor, High-performance liquid chromatographic assay of a central nervous system (CNS)-directed estradiol chemical delivery system and its application after intravenous administration to rats, Pharm. Res. 5: 172 (1988).CrossRefGoogle Scholar
  45. 45.
    M.H. Rahimy, J.W. Simpkins and N. Bodor, Tissue distribution of a brain-enhanced chemical delivery system for estradiol, submitted for publication, Drug Design and Delivery (1989).Google Scholar
  46. 46.
    G.T. Ross, Disorders of the ovary and female reproductive tract, in: “Textbook of Endocrinology,” J.D. Wilson and D.W. Foster, eds., W.B. Saunders Company, Philadelphia (1981).Google Scholar
  47. 47.
    J.A. Czaja, Body weight and growth rates throughout the guinea pig pregnancy: evidence for modulation by endogenous estrogens, Physiol. Behay. 30: 197 (1975).CrossRefGoogle Scholar
  48. 48.
    M.F. Tarttelin, Cyclical variations in food and water intake in ewes, J. Physiol. 195: 29 (1968).Google Scholar
  49. 49.
    M.F. Tarttelin and R.A. Gorski, Variations in food and water intake in normal and acyclic female rats, Physiol. Behay. 7: 847 (1971).CrossRefGoogle Scholar
  50. 50.
    J.A. Czaja, Ovarian influence on primate food intake: assessment of progesterone actions, Physiol. Behay. 21: 923 (1978).CrossRefGoogle Scholar
  51. 51.
    J.A. Czaja, Food rejection by female rhesus monkeys during the menstrual cycle and early pregnancy, Physiol. Behay. 14: 579 (1975).CrossRefGoogle Scholar
  52. 52.
    S.P. Dalvit, The effects of the menstrual cycle on patterns of food intake, Am. J. Clin. Nutr. 34: 1811 (1981).Google Scholar
  53. 53.
    P. Pliner and A.S. Fleming, Food intake, body weight and sweetness preferences over the menstrual cycle in humans, Physiol. Behay. 30: 663 (1983).CrossRefGoogle Scholar
  54. 54.
    T. Landau and I. Zucker, Estrogenic regulation of body weight in the female rats, Horm. Behay. 7: 29 (1976).CrossRefGoogle Scholar
  55. 55.
    J.F. McElroy and G.N. Wade, Short-and long-term effects of ovariectomy on food intake, body weight, carcass composition and brown adipose tissue in rats, Physiol. Behay. 39: 361 (1987).CrossRefGoogle Scholar
  56. 56.
    M.F. Tarttelin and R.A. Gorski, The effects of the ovarian steroids on food and water intake and body weight in the female rats, Acta Endronol. 72: 551 (1973).Google Scholar
  57. 57.
    J.H. Morton, H. Additon, R.G. Addison, L. Hunt, J.J. Sullivan, A clinical study of premenstrual tension, Am. J. Obstet. Gynecol. 65: 1182 (1953).Google Scholar
  58. 58.
    S.L. Smith and C. Sauder, Food cravings, depression and premenstrual problems, Psychosom. Med. 31: 281 (1969).Google Scholar
  59. J.W. Simpkins, W.R. Anderson, R. Dawson, Jr., A. Seth, M. Brewster, K.S. Estes and N. Bodor, Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol, Physiol. Behay. 44: 573 (1988).CrossRefGoogle Scholar
  60. 60.
    V.N. Luine, R.I. Khylchevskaya and B.S. McEwen, Effect of gonadal steroids on activity of monoamine oxidase and choline acetylase in rat brain, Brain Res. 86: 293 (1975).CrossRefGoogle Scholar
  61. 61.
    J.T. Coyle, D.L. Price and M.R. Delong, Alzheimer’s disease: a disorder of cortical cholinergic innervation, Science 219: 1184 (1983).CrossRefGoogle Scholar
  62. 62.
    V.N. Luine, Estradiol increases choline acetyltransferase activity in specific basal -forebrain nuclei and projection areas in female rats, Exp. Neurol. 89: 484 (1985).CrossRefGoogle Scholar
  63. 63.
    C.A. O’Malley, R.D. Hautamaki, M. Kelley, E.M. Meyer, Effects of ovariectomy and estradiol benzoate on high affinity choline uptake, Ach synthesis, and release from rat cerebral cortical synaptosomes, Brain Res. 403: 389 (1987).CrossRefGoogle Scholar
  64. 64.
    H.I. Kantor, C.M. Michael, H. Shore and H.W. Ludvigson, Administration of estrogens to older women, a psychometric evaluation, Am. J. Obstet. Gvnecol. 101: 58 (1968).Google Scholar
  65. 65.
    C.H. Michael, H.I. Kantor and H. Shore, Further psychometric evaluation of older women-the effect of estrogen administration, J. Gerontol. 25: 337 (1970).Google Scholar
  66. 66.
    H. Fillit, H. Weinreb, I. Cholst, V. Luine, B. McEwen, R. Amador and J. Zabriskie, Observations in a preliminary open trial of estradiol therapy for senile dementia-Alzheimer’s type, Psychoneuronedocrinol. 11: 337 (1986).CrossRefGoogle Scholar
  67. 67.
    B.W. Hackman and D. Galbraith, Replacement therapy with piperazine oestrone sulfate (“Harmogen”) and its effect on memory, Current Medical Research and Opinion 4: 303 (1976).CrossRefGoogle Scholar
  68. 68.
    M. Raskind, Biological parameters in the differential diagnosis of dementia and depression, in: “Biology and Treatment of Dementia in the Elderly,” C.A. Shamoian, Ed., American Psychiatric Press, Washington, D.C. (1983).Google Scholar
  69. 69.
    V. Chan-Palay, Y.S. Allen, W. Lang, V. Haesler and J.M. Polak, II. Cortical neurons immunoreactive with antisera against neuropeptide Y are altered in Alzheimer’s-type dementia, J. Comp. Neurol. 238: 391 (1985).Google Scholar
  70. 70.
    P. Davies, R. Katzman and R.D. Terry, Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer’s disease and Alzheimer’s senile dementia, Nature 288: 279 (1980).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • James W. Simpkins
    • 1
    • 2
  • Mohamad H. Rahimy
    • 1
    • 2
  • Nicholas Bodor
    • 3
    • 2
  1. 1.Departments of PharmacodynamicsUniversity of FloridaGainesvilleUSA
  2. 2.Medicinal ChemistryUniversity of FloridaGainesvilleUSA
  3. 3.College of Pharmacy and the Center for Drug Design and DeliveryUniversity of FloridaGainesvilleUSA

Personalised recommendations